C1 inhibitor (C1INH) is a serine protease inhibitor involved in the regulation of several proteolytic systems in plasma including the complement, contact, coagulation and fibrinolytic systems. Davis et al., Ann. Rev. Immunol., 6:595-628 (1988). C1INH is known to regulate those systems by forming covalent complexes with specific serine protease components of each system.
Several specific serine proteases whose activity are directly regulated by C1 inhibitor have been identified. For instance, C1INH is the only known inhibitor of C1r and C1s, both of which are activated fragments of the complement system component C1.
In addition, the art teaches that C1INH is the most important inhibitor of the contact system because C1INH is the primary inhibitor of both kallikrein and the activated forms of coagulation factor XII, including factor XIIa and factor XIIf (Hageman factor). Proud et al., Ann. Rev. Immunol., 6:49-83 (1988).
Deficiencies in C1INH are known to cause serious and potentially life-threatening diseases. The best characterized example of a C1INH deficiency is found in individuals with hereditary angioedema (HAE), also known as hereditary angioneurotic disorder, caused by a hereditary deficiency in the ability to produce C1INH. Individuals with symptoms of HAE exhibit recurrent, acute, local circumscribed edema of the skin or mucosa, primarily on the extremities, face, larynx and gastrointestinal tract. Davis et al., Ann. Rev. Immunol., 6:595-628 (1988).
Another distinct type of C1INH deficiency, termed acquired C1INH deficiency, occurs in individuals who synthesize normal amounts of C1INH, but cannot maintain sufficient concentrations of the inhibitor because of its increased catabolism. Individuals with acquired C1INH deficiency exhibit the symptoms of HAE. Whereas both HAE and acquired C1INH deficiency exhibit the typical laboratory profile of decreased levels of both C1INH and complement system components C4 and C2, the levels of complement system component C1q is decreased only in the acquired disease.
Presently, three distinct mechanisms have been proposed that create an acquired C1INH deficiency. First, a C1INH deficiency can be acquired when the amount of normally available C1INH is consumed by an excessive amount of complement and/or contact system activation. Some of the activated components of each of the complement and contact systems can bind and inactivate C1INH. In addition, activated contact system components can cleave C1INH into inactive fragments. Zuraw et al., J. Clin. Invest., 78:567-575 (1986).
Second, a C1INH deficiency can be acquired as the result of an anti-C1INH autoimmune reaction. In such a case, C1INH is synthesized, but anti-C1INH autoantibodies bind the inhibitor and thereby prevent its ability to regulate serine protease activity Third, a C1INH deficiency can be acquired as a result of C1INH being bound by complement-containing autoimmune complexes which are rapidly cleared from the circulation.
From the foregoing, it can be seen that a method for increasing the intravascular level of C1INH would be useful for treating disease caused by C1INH deficiencies. A method for increasing intravascular C1INH concentrations would be particularly useful as a prophylactic treatment for C1INH consumption due to acute complement and/or contact system activation.
Presently, the specific physiological mechanism(s) controlling the blood concentration of C1INH is not known. The primary site of C1INH synthesis during the acute phase reaction to blood trauma has been proposed to be the liver. Davis et al., Ann. Rev. Immunol., 6:595-628 (1988); Johnson et al., Science, 173-553-554 (1971). Complement, 4:244, A319 (1987). In contrast, the source of C1INH in response to localized, non-traumatic inflammation appears to be cells of the monocycle/macrophage lineage. For instance, several in vitro studies have suggested that cultured monocytes can be stimulated to synthesize C1INH by treatment with interferon gamma. See, Hamilton et al., Biochem. J., 242:809-815 (1987); Lotz et al., J. Immunol., 139:3382-3387 (1987); Lotz et al., J. Allerg. Clin. Immunol., 79:194, A280 (1987); and Lappin et al., Complement, 4:184, A160 (1987). In addition, the results of one in vitro study suggest that cultured hepatocytes synthesize C1INH in response to interferon gamma. Zuraw et al., Complement, 4:244, A319, 1987).
However, as is well known in the art, the results of in vitro studies obtained with interferon gamma do not predictably indicate that the same results will be obtained in vivo. For example, the treatment of cultured monocytes with interferon gamma results in an increase in the level of HLA-DR antigen expression on the surface of the monocytes. In contrast, administration of interferon gamma to a patient decreased the level of HLA-DR antigen expression by monocytes in the patient. Firestein et al., Arthrit. Rheum., 30:S115, E13 (1987).
To date there has been no study of interferon gamma's effects on C1INH levels in vivo. This is not surprising in view of the fact that interferon gamma, as it is presently understood, is described as an immunomodulator that regulates activation and growth of specific immune cells.